Several contraceptives which comprise synthetic progestogens and no estrogen are commercially available. These contraceptives, called Progestogen-Only Contraceptives (“POCs”), encompass implants, uterine delivery systems and pills.
POCs have the advantage of avoiding the combined administration of estrogens as compared to traditional contraceptive combined pills. POCs, however, display several major drawbacks. Because of their low contraceptive reliability, POCs have to be taken each day at the same time without a pill-free or placebo interval.
The bleeding patterns for women who take POCs may be also be altered significantly as compared to the natural menstrual cycle, since amenorrhea or unscheduled bleeding or spotting may occur. Accordingly, POCs are seldom used and are usually only indicated for women who cannot tolerate estrogen, for women in post-partum period, and for women who are breast-feeding (Amy, Tripathi, 2009, BMJ, 339, 563-568; Mandisk, 2008, OBSTETRIC MEDICINE, 1, 78-87).
Drospirenone (CAS: 67392-87-4; 6b,7b:15b,16b-Dimethylen-3-oxo-17α-pregn-4-ene-21,17-carbolactone) is a synthetic progestogen with a pharmacological profile very closely related to that of natural progesterone. Drospirenone (“DRSP”) is devoid of androgenic, glucocorticoid and antiglucocorticoid activity, but it does possess potent antimineralocorticoid and antiandrogenic properties. It has been shown that oral daily doses of at least 3 mg of drospirenone can inhibit ovulation over a single treatment cycle of 21 days. The combination of 3 mg drospirenone/30 μg ethinylestradiol may provide a reasonable contraceptive safety margin by inhibiting ovulation with a low frequency of follicular maturation (Rosenbaum et al., 2000, THE EUROPEAN JOURNAL OF CONTRACEPTION AND REPRODUCTIVE HEALTH CARE, 5, 16-24).
Drospirenone is thus an appropriate progestin ingredient which may avoid the side-effects occurring with conventional synthetic progestogens, such as weight gain and breast tenderness when combined with an estrogen for use as a contraceptive. DRSP is also likely to minimize fluid retention and to have neutral effects on metabolic and vascular risks (Blode et al., 2000, THE EUROPEAN JOURNAL OF CONTRACEPTION AND REPRODUCTIVE HEALTH CARE, 5,256-264; Sitruk-Ware, 2006, HUMAN REPRODUCTION UPDATE, 12, 169-178). It has been also reported that drospirenone may treat moderate acne because of its well-established anti-androgenic properties.
Drospirenone as a contraceptive ingredient is available only in oral combined pills such as those marketed under the name of Yasmin® (3 mg DRSP/30 μg ethinylestradiol), Yaz® (3 mg DRSP/20 μg ethinylestradiol) and Yasminelle® (3 mg DRSP/20 μg ethinylestradiol). These pills comprise ethinylestradiol, which acts to increase the ovulation inhibitory effect of drospirenone and to ensure contraception and cycle stability. International Application WO2008/031631 provides combined oral contraceptives in which drospirenone is used as a progestative agent and ethinylestradiol is replaced by the phytoestrogen 8-prenylnaringenin. These contraceptives may be included in modified release formulations of 8-prenylnaringenin and drospirenone, which may continuously distribute the active ingredients for the gastrointestinal transit time of generally 12 h-16 h.
The commercially available contraceptives Yasmin®, Yaz® and Yasminelle® comprise drospirenone in a micronized form which promotes its rapid dissolution in vitro and ensures its good oral bioavailability. It is also the case for Angeliq®, which is a hormone replacement medicament combining drospirenone and estradiol. However, such formulations are characterized by a high plasma concentration peak for drospirenone after oral intake. High plasma concentrations are not desirable in patients treated with drospirenone because of a correlation between high Cmax and certain undesirable side effects as well as poor general tolerance when hormonal levels fluctuate too much each and every day.
While contraceptive use of drospirenone in combination with estrogen has been demonstrated to avoid many of the adverse side-effects, such as weight gain and irregular bleeding, contraceptive use of POCs, which are devoid of estrogen, has been associated with a number of undesirable side effects, including unscheduled bleeding or spotting, irregularities in the amount and frequency of menstrual flow, and weight gain.
Unscheduled bleeding or spotting has been observed in women using POCs. Scheduled bleeding or spotting occurs during hormone free intervals (days 25-28±1), whereas unscheduled bleeding or spotting may occur while taking the active hormones (days 2-23). Bleeding irregularities are one of the prominent reasons that patients discontinue contraception, which increases the risk of unintended pregnancy.
Irregularities in amount and frequency of menstrual flow and weight gain have also been reported as side effects of POC contraceptive use. Such side effects have been observed with DMPA, a long acting reversible progestin-only contraceptive birth control drug that is injected every 3 months (Harel Z et al. Adolescents' reasons for and experience after discontinuation of the long-acting contraceptives Depo-Provera and Norplant. J ADOLESC HEALTH 1996; 19:118-23; Kaunitz A M. Injectable depot medroxyprogesterone acetate contraception: an update for U.S. clinicians. INT J FERTIL WOMENS MED 1998; 43(2):73-83; Keder et al. Compliance with depot medroxyprogesterone acetate: a randomized, controlled trial of intensive reminders. AM J OBSTET GYNECOL 1998; 179(3 Pt 1)):583-5; Fraser & Dennerstein. Depo-Provera use in an Australian metropolitan practice. MED J AUSTRALIA 1994; 160:553-6.1-6; Nutley & Danson. Treatment of bleeding problems associated with progestin-only contraceptives: survey results. ADV CONTRACEPT 1997; 13:419-28; Hill. Gynecology case challenge: vaginal bleeding in a woman taking an injectable contraceptive. MEDSCAPE WOMENS HEALTH 1998; 3(1):4).
POC treatment has also been associated with a weight gain. This is a particularly troubling for women with excess weight, i.e., women who are overweight or obese, since additional weight gain may increase their susceptibility to developing coronary heart diseases, high blood pressure, stroke, type 2 diabetes, abnormal blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea, obesity hypoventilation syndrome, infertility, gallstones, gout, and other diseases or conditions associated with excess weight or obesity.